Biomedical implants that facilitate communication/interaction with the surrounding tissue and/or circulatory system are rendered ineffective by the huge diffusion barrier and increased electrical resistance presented by the fibrous capsule. Examples of these devices include biomaterial implants, biosensors, implantable drug-delivery devices and tissue-engineering scaffolds. The foreign body response is characterized by enhanced recruitment of inflammatory cells. For successful implants, it is ideal to have the device surrounded and penetrated by highly vascularized tissue. Angiogenesis is the formation of new blood vessels from the existing vascular system. Both angiogenesis and inflammation are inescapable in vivo responses to all biomaterial implants. Most biomaterial implants are designed either to reduce inflammation or to improve vascularization. Although progress has been made, many studies overlook the important interconnectivity of inflammation with angiogenesis and focus on only simple in vitro outcomes. Indeed, eventual clinical success of biomaterials will require coping with the interconnectivity of the complex in vivo environment. There is emerging evidence that inflammatory cells regulate the functions of endothelial cells related to angiogenesis. However, the signals initiating angiogenesis in inflammation are complex and difficult to define. The proposed research addresses the hypothesis: the biomaterial-induced inflammatory response may be critical to control angiogenesis. Elucidating a clear physiological mechanism for angiogenesis in biomaterial-induced inflammation will provide new paradigms of biomaterial design and fabrication for the next generation of biomaterials. In order to test this hypothesis, a new class of biomaterials, hydrogels-fabricated from Polyethylene glycol (PEG)-cross-linked tyrosine-derived polycarbonate, has been synthesized and characterized. The hydrogel scaffolds will be made more bioactive to control inflammation and angiogenesis by introducing functional peptides on the polymers. A series of studies will be performed to investigate the role(s) of inflammation in angiogenesis on the hydrogel scaffolds. This study will have high impact on implantation-targeted biomaterial research, because elucidating a mechanism that initiates host inflammatory responses and the subsequent vascularization of biomaterial implants is high risk but very important. The identification of a clear mechanism will provide an efficient and realistic paradigm of the interconnectivity of inflammation with angiogenesis for the functional survival of biomaterial implants. This study will involve sophisticated bioengineering-based technical challenges, such as development of a new class of biomaterial scaffolds, fabrication of scaffold materials to be bioactive, and a quantitative imaging approach using multiphoton microscopy to measure multiple cell functions. The high risk nature of this work has necessitated several different approaches to generate the scaffolds and modify them for testing of the role of inflammation in angiogenesis and of angiogenesis in implant function and survival. PUBLIC HEALTH RELEVANCE: This project will optimize the inherent ability of the inflammatory process present in all biomaterial implant applications to 1) promote angiogenesis by utilizing bioactive molecules in the implant scaffold and 2) enhance design of the implant to release degradation products that direct angiogenesis. To overcome the difficulties in studying inflammatory and angiogenic responses to biomaterials, several high risk in vitro and in vivo methods will be utilized.